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Series GSE266389 Query DataSets for GSE266389
Status Public on May 16, 2024
Title Suppressing Aberrant Hedgehog Pathway and Overcoming Resistance to Smoothened Antagonists via Targeting Super-enhancer-driven Transcriptional Dependencies [RNA-seq]
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Aberrant activation of Hedgehog (Hh) signaling pathway plays important roles in both oncogenesis and targeted therapy of many cancers. The clinical application of FDA-approved Hh-targeted Smoothened inhibitor (SMOi) drugs is hindered due to the emergence of various primary or acquired drug resistance, indicating the need of novel anti-Hh therapies. Our previous studies demonstrate that epigenetic/transcriptional targeted therapies represent a promising direction for anti-Hh drug development. In this study, we identified CDK9 and CDK12, two transcription elongation regulators, as novel therapeutic targets for antagonizing the aberrant Hh pathway and overcoming SMOi resistance. CDK9 inhibition and CDK12 inhibition exhibited similarly potent anti-Hh activities when treating various SMOi responsive or resistant Hh-driven tumor models as previously reported BET inhibition or CDK7 inhibition. We also utilized SHH-subtype medulloblastoma (SHH-MB) as the representative Hh-driven cancer model to perform Super-enhancer (SE) analysis and elucidate the crucial roles of SE in Hh-driven oncogenesis and above-mentioned anti-Hh epigenetic/transcriptional targeted therapies. Furthermore, we identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the IGF pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target of multiple Hh-driven tumor models, including the SMOi-resistant ones. Collectively, our study demonstrates that the SE-driven transcriptional dependencies represent promising therapeutic vulnerabilities for suppressing the aberrant Hh pathway and overcoming the SMOi resistance. As CDK9 inhibitor and IRS inhibitor drugs have already entered human clinical trials for cancer treatment, our study provides comprehensive preclinical support for expanding their trials to Hh-driven cancers in near future.
 
Overall design mouse SHH-MB models SmoWT-MB and SMB56 were treated with SMO, BET, CDK7, CDK9, and CDK12 inhibitors with DMSO-treated controls. SHH-MB patient-derived xenograft (PDX) models SHH-MB_PDX1 were treated with BET, CDK7, CDK9, and CDK12 inhibitors with DMSO-treated controls. P60 cerebellum, P7 cerebellum, and SMOi-resistant model SmoWT-MB-GR cells were also collected. We then performed RNA-seq analysis to identify the gene expression profiling of the above samples.
 
Contributor(s) Sui Y, Wang T, Wang C, Tang Y
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Submission date May 01, 2024
Last update date May 16, 2024
Contact name Yi Sui
E-mail(s) suiyi12002@126.com
Organization name Shanghai Jiao Tong University School of Medicine
Street address South Chongqing Road
City Shanghai
ZIP/Postal code 200025
Country China
 
Platforms (3)
GPL21273 HiSeq X Ten (Mus musculus)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (60)
GSM8246121 SmoWT-MB, DMSO, 8h, in vitro, rep1
GSM8246122 SmoWT-MB, DMSO, 8h, in vitro, rep2
GSM8246123 SmoWT-MB, JQ1, 8h, in vitro, rep1
This SubSeries is part of SuperSeries:
GSE266391 Suppressing Aberrant Hedgehog Pathway and Overcoming Resistance to Smoothened Antagonists via Targeting Super-enhancer-driven Transcriptional Dependencies
Relations
BioProject PRJNA1106896

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE266389_ExVivo_56_WT_GDC_Count_FPKM.txt.gz 1.5 Mb (ftp)(http) TXT
GSE266389_ExVivo_PDX1_JQ1_THZ1_AZD_T531_Count_FPKM.txt.gz 2.0 Mb (ftp)(http) TXT
GSE266389_ExVivo_SmoWT_AZD_T531_Count_FPKM.txt.gz 1.1 Mb (ftp)(http) TXT
GSE266389_InVitro_56_WT_JQ1_THZ1_GDC_Count_FPKM.txt.gz 3.1 Mb (ftp)(http) TXT
GSE266389_InVitro_SMB56_AZD_SR_Count_FPKM.txt.gz 1.3 Mb (ftp)(http) TXT
GSE266389_InVivo_P60_P7_WT_Cerebellum_GDC_Count_FPKM.txt.gz 1.8 Mb (ftp)(http) TXT
GSE266389_SmoWT-GR_Count_FPKM.txt.gz 556.1 Kb (ftp)(http) TXT
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